Heterocyclic compounds and their uses

ABSTRACT

Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren&#39;s syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

This application claims the benefit of U.S. Provisional Application No.60/919,571, filed Mar. 23, 2007, which is hereby incorporated byreference.

The present invention relates generally to phosphatidylinositol 3-kinase(PI3K) enzymes, and more particularly to selective inhibitors of PI3Kactivity and to methods, of using such materials.

BACKGROUND OF THE INVENTION

Cell signaling via 3′-phosphorylated phosphoinositides has beenimplicated in a variety of cellular processes, e.g., malignanttransformation, growth factor signaling, inflammation, and immunity (seeRameh et al., J. Biol Chem, 274:8347-8350 (1999) for a review). Theenzyme responsible for generating these phosphorylated signalingproducts, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), wasoriginally identified as an activity associated with viral oncoproteinsand growth factor receptor tyrosine kinases that phosphorylatesphosphatidylinositol (PI) and its phosphorylated derivatives at the3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol2:358-60 (1992)).

The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), theprimary product of PI 3-kinase activation, increase upon treatment ofcells with a variety of stimuli. This includes signaling throughreceptors for the majority of growth factors and many inflammatorystimuli, hormones, neurotransmitters and antigens, and thus theactivation of PI3Ks represents one, if not the most prevalent, signaltransduction events associated with mammalian cell surface receptoractivation (Cantley, Science 296:1655-1657 (2002); Vanhaesebroeck et al.Annu. Rev. Biochem, 70: 535-602 (2001)). PI 3-kinase activation,therefore, is involved in a wide range of cellular responses includingcell growth, migration, differentiation, and apoptosis (Parker et al.,Current Biology, 5:577-99 (1995); Yao et al., Science, 267:2003-05(1995)). Though the downstream targets of phosphorylated lipidsgenerated following PI 3-kinase activation have not been fullycharacterized, it is known that pleckstrin-homology (PH) domain- andFYVE-finger domain-containing proteins are activated when binding tovarious phosphatidylinositol lipids (Steinmark et al., J Cell Sci,112:4175-83 (1999); Lemmon et al., Trends Cell Biol, 7:237-42 (1997)).Two groups of PH-domain containing PI3K effectors have been studied inthe context of immune cell signaling, members of the tyrosine kinase TECfamily and the serine/threonine kinases of the AGC family. Members ofthe Tec family containing PH domains with apparent selectivity forPtdIns (3,4,5)P₃ include Tec, Btk, Itk and Etk. Binding of PH to PIP₃ iscritical for tyrsosine kinase activity of the Tec family members(Schaeffer and Schwartzberg, Curr. Opin. Immunol. 12: 282-288 (2000))AGC family members that are regulated by PI3K include thephosphoinositide-dependent kinase (PDK1), AKT (also termed PKB) andcertain isoforms of protein kinase C (PKC) and S6 kinase. There arethree isoforms of AKT and activation of AKT is strongly associated withPI3K-dependent proliferation and survival signals. Activation of AKTdepends on phosphorylation by PDK1, which also has a3-phosphoinositide-selective PH domain to recruit it to the membranewhere it interacts with AKT. Other important PDK1 substrates are PKC andS6 kinase (Deane and Fruman, Annu. Rev. Immunol. 22_(—)563-598 (2004)).In vitro, some isoforms of protein kinase C (PKC) are directly activatedby PIP3. (Burgering et al., Nature, 376:599-602 (1995)).

Presently, the PI 3-kinase enzyme family has been divided into threeclasses based on their substrate specificities. Class I PI3Ks canphosphorylate *phosphatidylinositol (PI),phosphatidylinositol-4-phosphate, andphosphatidyl-inositol-4,5-biphosphate (PIP2) to producephosphatidylinositol-3-phosphate (PIP),phosphatidylinositol-3,4-biphosphate, andphosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ksphosphorylate PI and phosphatidyl-inositol-4-phosphate, whereas ClassIII PI3Ks can only phosphorylate PI.

The initial purification and molecular cloning of PI 3-kinase revealedthat it was a heterodimer consisting of p85 and p110 subunits (Otsu etal., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992)).Since then, four distinct Class I PI3Ks have been identified, designatedPI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalyticsubunit and a regulatory subunit. More specifically, three of thecatalytic subunits, i.e., p110α, p110β and p110δ, each interact with thesame regulatory subunit, p85; whereas p110γ interacts with a distinctregulatory subunit, p101. As described below, the patterns of expressionof each of these PI3Ks in human cells and tissues are also distinct.Though a wealth of information has been accumulated in recent past onthe cellular functions of PI 3-kinases in general, the roles played bythe individual isoforms are not fully understood.

Cloning of bovine p110α has been described. This protein was identifiedas related to the Saccharomyces cerevisiae protein: Vps34p, a proteininvolved in vacuolar protein processing. The recombinant p110α productwas also shown to associate with p85α, to yield a PI3K activity intransfected COS-1 cells. See Hiles et al., Cell, 70, 419-29 (1992).

The cloning of a second human p110 isoform, designated p110β, isdescribed in Hu et al., Mol Cell Biol, 13:7677-88 (1993). This isoformis said to associate with p85 in cells, and to be ubiquitouslyexpressed, as p110β mRNA has been found in numerous human and mousetissues as well as in human umbilical vein endothelial cells, Jurkathuman leukemic T cells, 293 human embryonic kidney cells, mouse 3T3fibroblasts, HeLa cells, and NBT2 rat bladder carcinoma cells. Such wideexpression suggests that this isoform is broadly important in signalingpathways.

Identification of the p110δ isoform of PI 3-kinase is described inChantry et al., J Biol Chem, 272:19236-41 (1997). It was observed thatthe human p110δ isoform is expressed in a tissue-restricted fashion. Itis expressed at high levels in lymphocytes and lymphoid tissues and hasbeen shown to play a key role in PI 3-kinase-mediated signaling in theimmune system (Al-Alwan et al. JI 178: 2328-2335 (2007); Okkenhaug et alJI, 177: 5122-5128 (2006); Lee et al. PNAS, 103: 1289-1294 (2006)).P1108 has also been shown to be expressed at lower levels in breastcells, melanocytes and endothelial cells (Vogt et al. Virology, 344:131-138 (2006) and has since been implicated in conferring selectivemigratory properties to breast cancer cells (Sawyer et al. Cancer Res.63:1667-1675 (2003)). Details concerning the P1106 isoform also can befound in U.S. Pat. Nos. 5,858,753; 5,822,910; and 5,985,589. See also,Vanhaesebroeck et al., Proc Nat. Acad Sci USA, 94:4330-5 (1997), andinternational publication WO 97/46688.

In each of the PI3Kα, β, and δ subtypes, the p85 subunit acts tolocalize PI 3-kinase to the plasma membrane by the interaction of itsSH2 domain with phosphorylated tyrosine residues (present in anappropriate sequence context) in target proteins (Rameh et al., Cell,83:821-30 (1995)). Five isoforms of p85 have been identified (p85α,p85β, p55γ, p55α and p50α) encoded by three genes. Alternativetranscripts of Pik3r1 gene encode the p85 α, p55 α and p50α proteins(Deane and Fruman, Annu. Rev. Immunol. 22: 563-598 (2004)). p85α isubiquitously expressed while p85β, is primarily found in the brain andlymphoid tissues (Volinia et al., Oncogene, 7:789-93 (1992)).Association of the p85 subunit to the PI 3-kinase p110α, β, or δcatalytic subunits appears to be required for the catalytic activity andstability of these enzymes. In addition, the binding of Ras proteinsalso upregulates PI 3-kinase activity.

The cloning of p110γ revealed still further complexity within the PI3Kfamily of enzymes (Stoyanov et al., Science, 269:690-93 (1995)). Thep110γ isoform is closely related to p110α and p110β (45-48% identity inthe catalytic domain), but as noted does not make use of p85 as atargeting subunit. Instead, p110γ binds a p101 regulatory subunit thatalso binds to the βγ subunits of heterotrimeric G proteins. The p101regulatory subunit for PI3 Kgamma was originally cloned in swine, andthe human ortholog identified subsequently (Krugmann et al., J BiolChem, 274:17152-8 (1999)). Interaction between the N-terminal region ofp101 with the N-terminal region of p110γ is known to activate PI3Kγthrough Gβγ. Recently, a p101-homologue has been identified, p84 orp87^(PIKAP) (PI3Kγ adapter protein of 87 kDa) that binds p110γ (Voigt etal. JBC, 281: 9977-9986 (2006), Suire et al. Curr. Biol. 15: 566-570(2005)). p87^(PIKAP) is homologous to p101 in areas that bind p110γ andGβγ and also mediates activation of p110γ downstream ofG-protein-coupled receptors. Unlike p101, p87^(PIKAP) is highlyexpressed in the heart and may be crucial to PI3Kγ cardiac function.

A constitutively active PI3K polypeptide is described in internationalpublication WO 96/25488. This publication discloses preparation of achimeric fusion protein in which a 102-residue fragment of p85 known asthe inter-SH2 (iSH2) region is fused through a linker region to theN-terminus of murine p110. The p85 iSH2 domain apparently is able toactivate PI3K activity in a manner comparable to intact p85 (Klippel etal., Mol Cell Biol, 14:2675-85 (1994)).

Thus, PI 3-kinases can be defined by their amino acid identity or bytheir activity. Additional members of this growing gene family includemore distantly related lipid and protein kinases including Vps34 TOR1,and TOR2 of Saccharomyces cerevisiae (and their mammalian homologs suchas FRAP and mTOR), the ataxia telangiectasia gene product (ATR) and thecatalytic subunit of DNA-dependent protein kinase (DNA-PK). Seegenerally, Hunter, Cell, 83:1-4 (1995).

PI 3-kinase is also involved in a number of aspects of leukocyteactivation. A p85-associated PI 3-kinase activity has been shown tophysically associate with the cytoplasmic domain of CD28, which is animportant costimulatory molecule for the activation of T-cells inresponse to antigen (Pages et al., Nature, 369:327-29 (1994); Rudd,Immunity, 4:527-34 (1996)). Activation of T cells through CD28 lowersthe threshold for activation by antigen and increases the magnitude andduration of the proliferative response. These effects are linked toincreases in the transcription of a number of genes includinginterleukin-2 (IL2), an important T cell growth factor (Fraser et al.,Science, 251:313-16 (1991)). Mutation of CD28 such that it can no longerinteract with PI 3-kinase leads to a failure to initiate IL2 production,suggesting a critical role for PI 3-kinase in T cell activation.

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin, have been widely used as PI 3-kinaseinhibitors. These compounds, however, are nonspecific PI3K inhibitors,as they do not distinguish among the four members of Class I PI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI 3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI 3-kinases is about11M (Fruman et al., Ann Rev Biochem, 67:481-507 (1998)). Hence, theutility of these compounds in studying the roles of individual Class IPI 3-kinases is limited.

Based on studies using wortmannin, there is evidence that PI 3-kinasefunction also is required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al., Proc Natl Acad SciUSA, 91:4960-64 (1994)). Moreover, it has been shown that wortmannin andLY294002 block neutrophil migration and superoxide release. However,inasmuch as these compounds do not distinguish among the variousisoforms of PI3K, it remains unclear from these studies which particularPI3K isoform or isoforms are involved in these phenomena and whatfunctions the different Class I PI3K enzymes perform in both normal anddiseased tissues in general. The co-expression of several PI3K isoformsin most tissues has confounded efforts to segregate the activities ofeach enzyme until recently.

The separation of the activities of the various PI3K isozymes has beenadvanced recently with the development of genetically manipulated micethat allowed the study of isoform-specific knock-out and kinase deadknock-in mice and the development of more selective inhibitors for someof the different isoforms. P110α and p110β knockout mice have beengenerated and are both embryonic lethal and little information can beobtained from these mice regarding the expression and function of p110alpha and beta (Bi et al. Mamm. Genome, 13:169-172 (2002); Bi et al. J.Biol. Chem. 274:10963-10968 (1999)). More recently, p110α kinase deadknock in mice were generated with a single point mutation in the DFGmotif of the ATP binding pocket (p110αD^(933A)) that impairs kinaseactivity but preserves mutant p110α kinase expression. In contrast toknock out mice, the knockin approach preserves signaling complexstoichiometry, scaffold functions and mimics small molecule approachesmore realistically than knock out mice. Similar to the p110α KO mice,p110αD^(933A) homozygous mice are embryonic lethal. However,heterozygous mice are viable and fertile but display severely bluntedsignaling via insulin-receptor substrate (IRS) proteins, key mediatorsof insulin, insulin-like growth factor-1 and leptin action. Defectiveresponsiveness to these hormones leads to hyperinsulinemia, glucoseintolerance, hyperphagia, increase adiposity and reduced overall growthin heterozygotes (Foukas, et al. Nature, 441: 366-370 (2006)). Thesestudies revealed a defined, non-redundant role for p110α as anintermediate in IGF-1, insulin and leptin signaling that is notsubstituted for by other isoforms. We will have to await the descriptionof the p110β kinase-dead knock in mice to further understand thefunction of this isoform (mice have been made but not yet published;Vanhaesebroeck).

P110γ knock out and kinase-dead knock in mice have both been generatedand overall show similar and mild phenotypes with primary defects inmigration of cells of the innate immune system and a defect in thymicdevelopment of T cells (Li et al. Science, 287: 1046-1049 (2000), Sasakiet al. Science, 287: 1040-1046 (2000), Patrucco et al. Cell, 118:375-387 (2004)).

Similar to p110γ, PI3K delta knock out and kinase-dead knock-in micehave been made and are viable with mild and like phenotypes. Thep110δ^(D910A) mutant knock in mice demonstrated an important role fordelta in B cell development and function, with marginal zone B cells andCD5+ B1 cells nearly undetectable, and B- and T cell antigen receptorsignaling (Clayton et al. J. Exp. Med. 196:753-763 (2002); Okkenhaug etal. Science, 297: 1031-1034 (2002)). The p110δ^(D910A) mice have beenstudied extensively and have elucidated the diverse role that deltaplays in the immune system. T cell dependent and T cell independentimmune responses are severely attenuated in p110δ^(D910A) and secretionof TH1 (INF-γ) and TH2 cytokine (IL-4, IL-5) are impaired (Okkenhaug etal. J. Immunol. 177: 5122-5128 (2006)). A human patient with a mutationin p110δ has also recently been described. A taiwanese boy with aprimary B cell immunodeficiency and a gamma-hypoglobulinemia ofpreviously unknown aetiology presented with a single base-pairsubstitution, m.3256G to A in codon 1021 in exon 24 of p110δ. Thismutation resulted in a mis-sense amino acid substitution (E to K) atcodon 1021, which is located in the highly conserved catalytic domain ofp110δ protein. The patient has no other identified mutations and hisphenotype is consistent with p110δ deficiency in mice as far as studied.(Jou et al. Int. J. Immunogenet. 33: 361-369 (2006)).

Isoform-selective small molecule compounds have been developed withvarying success to all Class I PI3 kinase isoforms (Ito et al. J. Pharm.Exp. Therapeut., 321:1-8 (2007)). Inhibitors to alpha are desirablebecause mutations in p110α have been identified in several solid tumors;for example, an amplification mutation of alpha is associated with 50%of ovarian, cervical, lung and breast cancer and an activation mutationhas been described in more than 50% of bowel and 25% of breast cancers(Hennessy et al. Nature Reviews, 4: 988-1004 (2005)). Yamanouchi hasdeveloped a compound YM-024 that inhibits alpha and delta equi-potentlyand is 8- and 28-fold selective over beta and gamma respectively (Ito etal. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).

P110β is involved in thrombus formation (Jackson et al. Nature Med. 11:507-514 (2005)) and small molecule inhibitors specific for this isoformare thought after for indication involving clotting disorders (TGX-221:0.007 uM on beta; 14-fold selective over delta, and more than 500-foldselective over gamma and alpha) (Ito et al. J. Pharm. Exp. Therapeut.,321:1-8 (2007)).

Selective compounds to p110γ are being developed by several groups asimmunosuppressive agents for autoimmune disease (Rueckle et al. NatureReviews, 5: 903-918 (2006)). Of note, AS 605240 has been shown to beefficacious in a mouse model of rheumatoid arthritis (Camps et al.Nature Medicine, 11: 936-943 (2005)) and to delay onset of disease in amodel of systemic lupus erythematosis (Barber et al. Nature Medicine,11: 933-935 (205)).

Delta-selective inhibitors have also been described recently. The mostselective compounds include the quinazolinone purine inhibitors (PIK39and IC87114). IC87114 inhibits p110δ in the high nanomolar range (tripledigit) and has greater than 100-fold selectivity against p110α, is 52fold selective against p110ε but lacks selectivity against p110γ(approx. 8-fold). It shows no activity against any protein kinasestested (Knight et al. Cell, 125: 733-747 (2006)). Using delta-selectivecompounds or genetically manipulated mice (p110δ^(D910A)) it was shownthat in addition to playing a key role in B and T cell activation, deltais also partially involved in neutrophil migration and primed neutrophilrespiratory burst and leads to a partial block of antigen-IgE mediatedmast cell degranulation (Condliffe et al. Blood, 106: 1432-1440 (2005);Ali et al. Nature, 431: 1007-1011 (2002)). Hence p110δ is emerging as animportant mediator of many key inflammatory responses that are alsoknown to participate in aberrant inflammatory conditions, including butnot limited to autoimmune disease and allergy. To support this notion,there is a growing body of p110δ target validation data derived fromstudies using both genetic tools and pharmacologic agents. Thus, usingthe delta-selective compound IC 87114 and the p110δ^(D910A) mice, Ali etal. (Nature, 431: 1007-1011 (2002)) have demonstrated that delta plays acritical role in a murine model of allergic disease. In the absence offunctional delta, passive cutaneous anaphylaxis (PCA) is significantlyreduced and can be attributed to a reduction in allergen-IgE inducedmast cell activation and degranulation. In addition, inhibition of deltawith IC 87114 has been shown to significantly ameliorate inflammationand disease in a murine model of asthma using ovalbumin-induced airwayinflammation (Lee et al. FASEB, 20: 455-465 (2006). These data utilizingcompound were corroborated in p110δ^(D910A) mutant mice using the samemodel of allergic airway inflammation by a different group (Nashed etal. Eur. J. Immunol. 37:416-424 (2007)).

There exists a need for further characterization of PI3Kδ function ininflammatory and auto-immune settings. Furthermore, our understanding ofPI3Kδ requires further elaboration of the structural interactions ofp110δ, both with its regulatory subunit and with other proteins in thecell. There also remains a need for more potent and selective orspecific inhibitors of PI3K delta, in order to avoid potentialtoxicology associated with activity on isozymes p110 alpha (insulinsignaling) and beta (platelet activation). In particular, selective orspecific inhibitors of PI3Kδ are desirable for exploring the role ofthis isozyme further and for development of superior pharmaceuticals tomodulate the activity of the isozyme.

SUMMARY

The present invention comprises a new class of compounds having thegeneral formula

which are useful to inhibit the biological activity of human PI3Kδ.Another aspect of the invention is to provide compounds that inhibitPI3Kδ selectively while having relatively low inhibitory potency againstthe other PI3K isoforms. Another aspect of the invention is to providemethods of characterizing the function of human PI3Kδ. Another aspect ofthe invention is to provide methods of selectively modulating humanPI3Kδ activity, and thereby promoting medical treatment of diseasesmediated by PI3Kδ dysfunction. Other aspects and advantages of theinvention will be readily apparent to the artisan having ordinary skillin the art.

DETAILED DESCRIPTION

One aspect of the present invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Y is N(R¹¹), O or S;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₁₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,—NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), C(O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(a)N(R^(a))C(═O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), OC(═O)NR^(a)R^(a), —OC(═O)N(a)S(═O)₂R^(a),—OC₂₋₆alkylNR^(a), —S(═O)R^(a), —S(═O)₂R^(a), S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a); —NR^(a)R^(a),N(R^(a))C(═O)R^(a)N(R^(a))C(═O)OR^(a), N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle are additionally substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(a)S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR⁸, SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR², —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is H or C₁₋₄alkyl;

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the present invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Y is N(R¹), O or S;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(—O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,—NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆-spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(a)S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), SR^(a), S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a)N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), C(═O)OR^(a),C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a), —C(═O)R^(a),—C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a1)N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is H or C₁₋₄alkyl;

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the present invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Y is N(R¹¹), O or S;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC, alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyland C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC20C₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a)N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,—NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),COa, CO)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(—O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), S(═O)R^(a),S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —OC(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—C(═O)R^(a), —C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), C(═O)OR^(a),C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), S(═O)₂N(a)C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), N(R^(a))C(═O)R^(a),N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is H or C₁₋₄alkyl;

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the present invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Y is N(R¹¹), O or S;

n is 0, 1, 2 or 3;

R¹ is a direct-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl, heterocycle,—(C₁₋₃alkyl)heteroaryl, —(C₁₋₃alkyl)heterocycle,—O(C₁₋₃alkyl)heteroaryl, —O(C₁₋₃alkyl)heterocycle,—NR^(a)(C₁₋₃alkyl)heteroaryl, —NR^(a)(C₁₋₃alkyl)heterocycle,—(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyl and —NR^(a)(C₁₋₃alkyl)phenyl allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(a)S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(NR^(a))NR^(a)R^(a),OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—C(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is H or C₁₋₄alkyl;

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the invention relates to compounds having thestructure:

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is C(R⁹) or N;

X² is C(R¹⁰) or N;

Y is N(R¹¹), O or S;

n is 0, 1, 2 or 3;

R¹ is a saturated, partially-saturated or unsaturated 5-, 6- or7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms selectedfrom N, O and S, but containing no more than one O or S, wherein theavailable carbon atoms of the ring are substituted by 0, 1 or 2 oxo orthioxo groups, wherein the ring is. substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl;

R² is selected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), —C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² isselected from C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, allof which are substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I and C₁₋₄alkyl;

R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl;

R⁴ is, independently, in each instance, halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl orC₁₋₄haloalkyl;

R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl;

R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁷ is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are substituted by0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br,Cl, F, I and C₁₋₆alkyl;

R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a)N(R^(a))C(O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl;

R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),C(═O)OR^(a), —C(O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), a—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a)N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);

R¹⁰ is H, C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a),C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a);

R¹¹ is H or C₁₋₄alkyl;

R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, X¹ is C(R⁹) and X² is N.

In another embodiment, in conjunction with any of the above or belowembodiments, X¹ is C(R⁹) and X² is C(R¹⁰).

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl substituted by 0 or 1 R² substituents, and thephenyl is additionally substituted by 0, 1, 2 or 3 substituentsindependently selected from halo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl,OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is phenyl substituted by R², and the phenyl isadditionally substituted by 0, 1, 2 or 3 substituents independentlyselected from halo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl,NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is selected from 2-methylphenyl, 2-chlorophenyl,2-trifluoromethylphenyl, 2-fluorophenyl and 2-methoxyphenyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is a direct-bonded or oxygen-linked saturated,partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 0, 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the ring is substituted by 0 or 1 R²substituents, and the ring is additionally substituted by 1, 2 or 3substituents independently selected from halo, nitro, cyano, C₁₋₄alkyl,OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl andC₁₋₄haloalkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is an unsaturated 5- or 6-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹ is selected from pyridyl and pyrimidinyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is selected from halo, C₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), OC(═O)NR^(a)R^(a), —OC(═O)N(a)S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), SR^(a), CS(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a),—N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R³ is selected from F, Cl, C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl,heteroaryl and heterocycle are additionally substituted by 0, 1, 2 or 3substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I andC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁵ is, independently, in each instance, H, halo, C₁₋₆alkyl,C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groupstogether form a C₃₋₆spiroalkyl substituted by 0, 1, 2 or 3 substituentsselected from halo, cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl,OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁵ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, one R⁵ is S-methyl, the other is H.

In another embodiment, in conjunction with any of the above or belowembodiments, at least one R⁵ is halo, C₁₋₆alkyl, C₄haloalkyl, orC₁₋₆alkyl substituted by 1, 2 or 3 substituents selected from halo,cyano, OH, OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl, OC 4alkyl, NH₂,NHC₁₋₄alkyl, N(C₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NR^(b)R^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NH₂.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁶ is NHC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is selected from C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle aresubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is selected from C₁₋₆haloalkyl, Br, Cl, F, I andC₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁷ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is selected from C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a),NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle,wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle areadditionally substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), S(═O)₂N(R^(a))C(═O)OR^(a) and—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is NR^(a)R^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁸ is selected from C₁₋₃haloalkyl, Br, Cl, F and C₁₋₆alkyl.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(a)S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkyl alkylOR^(a), C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl,phenyl, benzyl, heteroaryl and heterocycle are additionally substitutedby 0, 1, 2 or 3 substituents selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))C(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R⁹ is a saturated, partially-saturated or unsaturated 5-,6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atomsselected from N, O and S, but containing no more than one O or S,wherein the available carbon atoms of the ring are substituted by 0, 1or 2 oxo or thioxo groups, wherein the ring is substituted by 0, 1, 2, 3or 4 substituents selected from halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂ alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R¹⁰ is H.

In another embodiment, in conjunction with any of the above or belowembodiments, R¹⁰ is cyano, nitro, CO₂R^(a), C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a).

In another embodiment, in conjunction with any of the above or belowembodiments, R¹¹ is H.

Another aspect of the invention relates to a method of treatingPI3K-mediated conditions or disorders.

In certain embodiments, the PI3K-mediated condition or disorder isselected from rheumatoid arthritis, ankylosing spondylitis,osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases,and autoimmune diseases. In other embodiments, the PI3K-mediatedcondition or disorder is selected from cardiovascular diseases,atherosclerosis, hypertension, deep venous thrombosis, stroke,myocardial infarction, unstable angina, thromboembolism, pulmonaryembolism, thrombolytic diseases, acute arterial ischemia, peripheralthrombotic occlusions, and coronary artery disease. In still otherembodiments, the PI3K-mediated condition or disorder is selected fromcancer, colon cancer, glioblastoma, endometrial carcinoma,hepatocellular cancer, lung cancer, melanoma, renal cell carcinoma,thyroid carcinoma, cell lymphoma, lymphoproliferative disorders, smallcell lung cancer, squamous cell lung carcinoma, glioma, breast cancer,prostate cancer, ovarian cancer, cervical cancer, and leukemia. In yetanother embodiment, the PI3K-mediated condition or disorder is selectedfrom type II diabetes. In still other embodiments, the PI3K-mediatedcondition or disorder is selected from respiratory diseases, bronchitis,asthma, and chronic obstructive pulmonary disease. In certainembodiments, the subject is a human.

Another aspect of the invention relates to the treatment of rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases or autoimmune diseases comprising thestep of administering a compound according to any of the aboveembodiments.

Another aspect of the invention relates to the treatment of rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases and autoimmune diseases, inflammatorybowel disorders, inflammatory eye disorders, inflammatory or unstablebladder disorders, skin complaints with inflammatory components, chronicinflammatory conditions, autoimmune diseases, systemic lupuserythematosis (SLE), myestenia gravis, rheumatoid arthritis, acutedisseminated encephalomyelitis, idiopathic thrombocytopenic purpura,multiples sclerosis, Sjoegren's syndrome and autoimmune hemolyticanemia, allergic conditions and hypersensitivity, comprising the step ofadministering a compound according to any of the above or belowembodiments.

Another aspect of the invention relates to the treatment of cancers thatare mediated, dependent on or associated with p110δ activity, comprisingthe step of administering a compound according to any of the above orbelow embodiments.

Another aspect of the invention relates to the treatment of cancers areselected from acute myeloid leukaemia, myelo-dysplastic syndrome,myelo-proliferative diseases, chronic myeloid leukaemia, T-cell acutelymphoblastic leukaemia, B-cell acute lymphoblastic feukaemia,non-hodgkins lymphoma, B-cell lymphoma, solid tumors and breast cancer,comprising the step of administering a compound according to any of theabove or below embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of rheumatoid arthritis, ankylosingspondylitis, osteoarthritis, psoriatic arthritis, psoriasis,inflammatory diseases, and autoimmune diseases.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising a minimum of a and amaximum of P carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Saturated, partially saturated or unsaturated” includes substituentssaturated with hydrogens, substituents completely unsaturated withhydrogens and substituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′=O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or .” (sometimesreferred to as Markush groups). When this language is used in thisapplication, unless otherwise stated it is meant to include the group asa whole, or any single members thereof, or any subgroups thereof. Theuse of this language is merely for shorthand purposes and is not meantin any way to limit the removal of individual elements or subgroups asneeded.

EXPERIMENTAL

The following abbreviations are used:

aq.—aqueousBINAP—2,2′-bis(diphenylphosphino)-1,1′-binaphthylcond—concentratedDCM dichloromethane

DMF—N,N-dimethylformamide

Et₂O—diethyl etherEtOAc—ethyl acetateEtOH—ethyl alcoholh—hour(s)min—minutesMeOH—methyl alcoholrt room temperaturesatd—saturatedTHF—tetrahydrofuran

General

Reagents and solvents used below can be obtained from commercialsources. ¹H-NMR spectra were recorded on a Bruker 400 MHz and 500 MHzNMR spectrometer. Significant peaks are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) andnumber of protons. Mass spectrometry results are reported as the ratioof mass over charge, followed by the relative abundance of each ion (inparentheses Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Agilent 1100 series LC/MSD electrospray massspectrometer. All compounds could be analyzed in the positive ESI modeusing acetonitrile:water with 0.1% formic acid as the delivery solvent.Reverse phase analytical HPLC was carried out using a Agilent 1200series on Agilent Eclipse XDB-C18 5 μm column (4.6×150 mm) as thestationary phase and eluting with acetonitrile:H₂O with 0.1% TFA.Reverse phase semi-prep HPLC was carried out using a Agilent 1100 Serieson a Phenomenex Gemini™ 10 μm C18 column (250×21.20 mm) as thestationary phase and eluting with acetonitrile:H₂O with 0.1% TFA.

A mixture of 2-chloro-quinoline-3-carbaldehyde (1 eq), arylboronic acid(1.1 eq), tetrakis(triphenylphosphine)palladium (5 mol %), and sodiumcarbonate (2M aq. Sol., 5.0 eq) in CH₃CN-water (3:1, 0.1 M) was heatedat 100° C. under N₂ for several hours. The mixture was partitionedbetween EtOAc and H₂O, the organic layer was separated, and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedover Na₂SO₄, filtered, concentrated under reduced pressure, and purifiedby column chromatography on silica gel using 0% to 25% gradient of EtOAcin hexane to provide 2-arylquinoline-3-carbaldehydes.

Solid sodium borohydride (1.5 eq) was added to a solution of2-arylquinoline-3-carbaldehyde (1 eq) in THF (0.5M) at 0° C. and themixture was stirred at 0° C. for 2 h. The reaction was quenched byaddition of water. The aqueous layer was extracted with EtOAc (3 times).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel using 50% of EtOAc in hexane to provide(2-arylquinolin-3-yl)methanols.

(2-Arylquinolin-3-yl)methanol (1 eq) in CHCl₃ (0.25M) was treated withSOCl₂ (5 eq) at rt for 2 h. Solvents were removed under reduced pressureand the residue was partitioned between EtOAc and saturated aq. NaHCO₃solution. The organic layer was separated, washed with water and brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was purified by column chromatography on a Redi-Sep™column using 0 to 100% gradient of EtOAc in hexane to provide3-(chloromethyl)-2-arylquinolines.

To a solution of 3-(chloromethyl)-2-arylquinoline (1 eq) in DMSO (0.25M) was added NaN₃ (3 eq) at rt and the mixture was stirred for 4 h atrt. The mixture was diluted with water, extracted with EtOAc (2 times)and the combined organic layers were washed with water (2 times), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and themixture was then stirred under H₂ balloon over night. The mixture wasfiltered through a celite pad followed by removal of solvents to give(2-arylquinolin-3-yl)methanamines.

To a stirring solution of 3-(chloromethyl)-2-arylquinoline (1 eq) in 16mL of DMF was added NaN₃ (2 eq) at rt. The mixture was stirred at rt for1 h. The mixture was partitioned between EtOAc and H₂O. The organiclayer was dried over MgSO₄, filtered, and concentrated under reducedpressure to provide 3-(azidomethyl)-2-arylquinolines. The crude productwas carried on without purification for the next step. To a stirringsolution of 3-(azidomethyl)-2-arylquinoline in THF-H₂O (4:1, 0.21 M) wasadded dropwise PMe₃ (1.0 M solution in THF, 1.2 eq) at rt and themixture was stirred at rt for 1 h. To the mixture was added EtOAc andthe mixture was extracted with 1N HCl (2 times). The combined extractswere neutralized with solid sodium bicarbonate, and extracted with EtOAc(2 times). The combined organic extracts were dried over MgSO₄,filtered, and concentrated under reduced pressure to give dark syrup.The crude product was purified by column chromatography on a Redi-Sep™column using 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂as eluent to provide (2-arylquinolin-3-yl)methanamines.

A mixture of 2-arylquinoline-3-carbaldehyde (1 eq), DCE (0.2 M), andPMBNH₂ (1.5 eq) was stirred at rt. After 1 h, to the mixture was addedNaBH(OAc)₃ (3 eq) and the mixture was stirred at 50° C. for 2 h. To themixture was added saturated aq. NaHCO₃ and the mixture was stirred for15 min. The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂ (2 times). The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on aRedi-Sep™ column using 0 to 100% gradient of EtOAc in hexane to provideN-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamines.

A mixture of N-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamine (1 eq)and ammonium cerium(iv) nitrate (3.5 eq) in CH₃CN—H₂O (2:1, 0.22M) wasstirred at rt for 24 h. To the mixture wad added 0.5M HCl (12 eq) andthe mixture was washed with CH₂Cl₂ (3 times) to remove4-methoxybenzaldehyde produced. The organic fraction was then extractedwith 0.5M HCl (2 times). The combined acidic aqueous layer was basifiedto pH 9.0 with 2N HaOH. The resulting precipitate was collected byfiltration. The crude product was purified by column chromatography on aRedi-Sep™ column using 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1)in CH₂Cl₂ as eluent to provide (2-arylquinolin-3-yl)methanamines.

To a mixture of 2-phenylquinoline-3-carbaldehyde (1.0 eq) in THF (0.28M)at 0° C. was added dropwise a solution of a Grignard reagent (3 M, 2 eq)and the reaction was stirred overnight before being quenched with NH₄Clsaturated solution. The mixture was extracted with EtOAc (2×10 mL) andthe combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (eluent: EtOAc/hexane, 1/1) to provide1-(2-phenylquinolin-3-yl)alcohols.

Example 1 Preparation of5-Chloro-N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrimidine-2,4-diamine

A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine(0.050 g, 0.18 mmol), and 4,5-dichloro-2-aminopyrimidine (0.029 g, 0.18mmol, 1 eq) were stirred in 1-pentanol (0.9 mL) at 80° C. for 4 days.After purification,5-chloro-N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrimidine-2,4-diamine[PI3Kδ IC₅₀32 165 nM] was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.18 (1H, s), 7.86 (1H, d, J=7.8 Hz), 7.72 (1H, s),7.45-7.64 (7H, m), 7.28 (1H, t, J=5.9 Hz), 6.02 (2H, s), 4.46 (2H, d,J=18.8 Hz), 2.65 (3H, s) Mass Spectrum (ESI) m/e=410.0 and 412.1 (M+1)

Example 2 Preparation ofN4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)-methyl)pyrimidine-4,6-diamine

Prepared according to Procedure H using8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.035 g, 0.11mmol), 4,6-diaminopyrimidine hydrochloride (0.032 g, 0.22 mmol, 2 eq)and DIEA (0.55 mL, 2.2 mmol, 20 eq) in ethanol (1 mL).N4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrimidine-4,6-diamine[PI3Kδ IC₅₀=6868 nM] was obtained after purification as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32 (1H, s), 8.05 (1H, dd, J=8.4, 1.0Hz), 7.95 (1H, dd, J=7.4, 1.2 Hz), 7.84 (1H, s), 7.51-7.67 (5H, m), 7.24(1H, s), 6.19 (2H, s), 5.32 (1H, s), 4.33 (1H, s) Mass Spectrum (ESI)m/e=396.1 and 398.0 (M+1)

Examples 3 and 4 Preparation ofN4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2,4-diamineandN2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine:

A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (81.1mg, 0.261 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (51.6 mg,0.261 mmol), and DIEA (0.09 mL, 0.52 mmol, 2 eq) in 1-pentanol (1.3 mL)was stirred at 80° C. for 30 min. The mixture was transferred to apressure vessel and ammonia gas was bubbled through the mixture at rtfor 15 min. The mixture was stirred at 100° C. 14 h. The mixture wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on a 40 g of Redi-Sep™ column using 0 to 100%gradient of EtOAc in hexane over 14 min as eluent to provideN4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine[PI3Kδ IC₅₀=127 nM] as light yellow solid (Example 3) andN2-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-5-(trifluoromethyl)-pyrimidine-2,4-diamine[PI3Kδ IC₅₀=2825 nM] (Example 4) as light yellow solid. For Example 3:¹H NMR (DMSO-d₆) δ ppm 8.12 (1H, s), 8.01 (1H, d, J=0.8 Hz), 7.82 (1H,d, J=8.2 Hz), 7.43-7.65 (6H, m), 7.17 (1H, t, J=5.7 Hz), 6.57 (2H, br.s.), 4.51 (2H, t, J=5.9 Hz), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1(M+1). For Example 4: ¹H NMR (DMSO-d₆) δ ppm 8.17-8.28 (1H, m), 8.00(1H, s), 7.85 (1H, d, J=7.8 Hz), 7.23-7.72 (7H, m), 6.68 (2H, s), 4.39(2H, s), 2.65 (3H, s); Mass Spectrum (ESI) m/e=444.1 (M+1).

Example 56-Chloro-N-((8-chloro-2-phenylquinolin-3-yl)methyl)-5-methoxypyrimidin-4-amine

A mixture of (8-chloro-2-phenylquinolin-3-yl)methanamine (0.035 g, 0.13mmol) in n-butanol (3 mL) was treated with DIEA (0.046 mL, 0.26 mmol,2.0 eq) followed with 4,6-dichloro-5-methoxypyrimidine (0.025 g, 0.14mmol, 1 eq) at 100° C. for 8 h. The reaction mixture was concentratedand purified by column chromatography on a Redi-Sep™ column using 0 to100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ as eluent toprovide 6-chloro-N-((8-100chloro-2-phenylquinolin-3-yl)methyl)-5-methoxypyrimidin-4-amine as awhite solid. ¹H-NMR (DMSO-d⁶) δ ppm 8.33 (s, 1H), 8.20 (t, 1H),8.02-8.04 (m, 1H), 7.99 (s, 1H), 7.93-7.95 (m, 1H), 7.70 (d, J=6.60,1H), 7.46-7.61 (m, 1H), 4.73 (d, J=5.71, 2H), 2.51 (s, 3H), MassSpectrum (ESI) m/e=412 (M+1).

Example 65-chloro-N4-((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)pyrimidine-2,4-diamine

A mixture of (1S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine(0.090 g, 0.32 mmol) in n-butanol (3 mL) was treated with DIEA (0.11 mL,0.64 mmol, 2.0 eq), followed with 4,5-dichloropyrimidin-2-amine (0.062g, 0.38 mmol, 1.2 eq) at 100° C. for 8 h. The reaction mixture wasconcentrated and purified by column chromatography on a Redi-Sep™ columnusing 0 to 100% gradient of CH₂Cl₂:MeOH:NH₄OH (89:9:1) in CH₂Cl₂ aseluent to provide5-chloro-N4-((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)pyrimidine-2,4-diamine[PI3Kδ IC₅₀=105 nM] as a white solid. ¹H-NMR (DMSO-d⁶) δ ppm 8.65-8.76(m, 1H), 8.53 (s, 1H), 8.11-8.20 (m, 1H), 8.07 (d, J=1.96 Hz, 1H),7.91-8.00 (m, 2H), 7.86 (s, 1H), 7.62 (t, J=8.02 Hz, 1H), 7.51-7.58 (m,1H), 6.03-6.25 (m, 1H), 1.38-1.63 (d, J=7.04, 3H), Mass Spectrum (ESI)m/e=412 (M+1).

Example 7

To 1-(2-chlorophenyl)ethanone (11.9 g, 76.97 mmol) in CH₂Cl₂ (140 ml)Pyridinium tribromide (29.5 g, 92.4 mmol) was added. The mixture wasstirred at room temperature for 4 hrs. The mixture was partitionedbetween CH₂Cl₂ and H₂O. The combined organic layers were dried,concentrated, and flash chromatography of the residue over silica gel,using 3:7 CH₂Cl₂-hexane, gave 2-bromo-1-(2-chlorophenyl)ethanone, ¹H-NMR(CDCl₃) δ 7.58 (d, J=7.4 Hz, 1H), 7.43-7.52 (m, 2H), 7.40-7.36 (m, 1H),4.53 (s, 2H). Mass Spectrum (ESI) m/e=234.9 (M+1).

To pyridine (2.1 ml, 26 mmol) in EtOH (60 ml) was added2-bromo-1-(2-chlorophenyl)ethanone (6.1 g, 26 mmol) in EtOH (40 ml)dropwise over 10 min. The resulting mixture was heated at 60-70° C. for1 hour and cooled to room temperature. To the mixture were addedpyridine (1.25 ml), 2-amino-3-chlorobenzaldehyde (3.72 g, 24.0 mmol) andDMAP (0.05 g, cat.). The mixture was heated at reflux for 48 hrs. Thereaction mixture was cooled to room temperature and pyrrolidine (4.60ml, 55.0 mmol) was added. After heating at. reflux overnight, theresulting mixture was concentrated. The residue was partitioned betweensaturated aqueous NaHCO₃ and CH₂Cl₂. The combined organic layers weredried, concentrated. Flash chromatography of the residue over silicagel, using 3:7 EtOAc-hexane, gave8-chloro-2-(2-chlorophenyl)-quinolin-3-amine, ¹H-NMR (DMSO-d⁶) δ 7.67(d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.46 (d,J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 5.32 (br, 2H). MassSpectrum (ESI) m/e=289.0 (M+1).

8-chloro-2-(2-chlorophenyl)quinolin-3-amine (3.5 g, 12 mmol) wasdissolved in acetonitrile (49.0 ml) and Acetic acid (3 ml) at roomtemperature, HCl (cond. 3 ml, 85 mmol) was added to afford a creamymixture. At 0° C. a solution of sodium nitrite (1.0 g, 15 mmol) in 2.0mL of water was added dropwise over 1 min. The temperature rose to 5° C.during the addition. Stirring was continued for 30 min. A saturatedsolution of SO₂ (16 g, 254 mmol) in acetic acid (30 ml, 520 mmol) waspoured into the reaction mixture. Then, a solution of copper (II)chloride dihydrate (1.0 g, 6 mmol) in 1.25 ml of water was added. Afterstirring for 2.5 h the formed solids in the mixture were filtered andrinsed with 6 mL of acetonitrile, 6 mL of water and 6 mL ofacetonitrile. The solids were dried to afford8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonyl chloride, ¹H-NMR(DMSO-d⁶) δ 8.88 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.97 (d, J=7.3 Hz,1H), 7.64 (t, J=7.9 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.3 Hz,1H), 7.40 (t, J=7.3 Hz, 1H), 7.33 (t, J=7.3 Hz, 1H). Mass Spectrum (ESI)m/e=372.0 (M+1).

The mixture of 8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonyl chloride(2.3 g, 6.2 mmol), ammonium hydroxide (50 ml) and acetonitrile (50 ml)in a sealed flask was stirred and heated at 100° C. overnight.Evaporation of the solvents and solid was filtered and rinsed withwater. The solids were dried and collected as pure product8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamide, ¹H-NMR (DMSO-d⁶) δ9.11 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 8.15 (d, J=7.4 Hz, 1H), 7.78 (t,J=8.0 Hz, 1H), 7.62 (s, 2H), 7.40-7.59 (m, 4H). Mass Spectrum (ESI)m/e=352.9 (M+1).

The flask was charged with tris(dibenzylideneacetone)dipalladium (0)chloroform adduct (53.2 mg, 51.4 μmol), cesium carbonate (402 mg, 1.23mmol), 4-bromo-picolinamide (103.4 mg, 0.514 mmol),8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamide (200 mg, 0.566 mmol),tBuXPhos (37.0 mg, 77.2 μmol) and filled with N₂. Then toluene (15.0 ml)was added and N₂ was bubbled through the mixture for 10 minutes. Themixture was heated at 100° C. for 16 hours. The mixture was cooled toroom temperature, evaporation of the solvent, diluted with CH₂Cl₂-MeOH(1:1, 25 mL), filtered through a pad of Celite™. The mixture wasconcentrated, and the residue was diluted with MeOH. The solution waspurified by HPLC, 20%-70% of B in 35 min. The collected fractions wereconcentrated and neutralized by adding aq. NaHCO₃ Filtration and rinsewith water gave4-(8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamido)picolinamide,¹H-NMR (MeOD) δ 9.33 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.8 Hz,1H), 7.74 (t, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.36-7.50 (m, 6H), 7.08 (d,J=8.0 Hz, 1H). Mass Spectrum (ESI) m/e=472.9 (M+1).

Example 8

The flask was charged with(2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (100.0 mg, 0.354mmol), obtained from A-1216 US PSP, procedure D, 4-bromopicolinamide (92mg, 0.460 mmol), diisopropylethylamine (0.080 ml, 0.460 mmol) and1-butanol (2.0 ml) and sealed. The mixture was subjected to microwave at180° C. for 4 hrs. After cooled to room temperature, the mixture wasconcentrated, and the residue was diluted with MeOH. The solution waspurified by HPLC, 25%-45% of B in 35 min. The collected fractions wereconcentrated and dissolved in CH₂Cl₂, neutralized by washing with aq.NaHCO₃ The CH₂Cl₂ layer was dried, concentrated and gave4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methylamino)picolinamide,¹H-NMR (MeOD) δ 8.21 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.71 (d, J=8.0 Hz,1H), 7.41-7.62 (m, 6H), 7.20 (d, J=2.4 Hz, 1H), 6.50 (dd, J=5.6, 2.4 Hz,1H) 4.42 (d, J=11.0 Hz, 1H), 4.27 (d, J=11.0 Hz, 1H), 2.73 (s, 1H). MassSpectrum (ESI) m/e=403.1 (M+1).

Example 9 Preparation ofN4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamine2-Chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidin-4-amine

A mixture of 2,4-dichloro-5-fluoropyrimidine (0.06548 g, 0.3922 mmol),8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (0.1189 g, 0.3922mmol), and n,n-diisopropylethylamine (0.1366 ml, 0.7843 mmol) in 2 ml of1-pentanol was stirred at 80° C. After 2 hr at 80° C., the mixture wascooled to room temperature and concentrated under reduced pressure togive a yellow syrup. The crude mixture was purified by columnchromatography on a 40 g of Redi-Sep™ column using 0-100% gradient ofEtOAc in hexane over 14 min as eluent to give the recovered reactant,2-chloro-N-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidin-4-amineas an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.58 (1H, br.s.), 8.48 (1H, s), 8.03-8.12 (2H, m), 7.97 (1H, dd, J=7.3, 1.0 Hz), 7.64(1H, t, J=7.8 Hz), 7.56 (1H, dd, J=7.6, 1.5 Hz), 7.40-7.51 (3H, m),4.46-4.64 (2H, m); LC-MS (ESI) m/z 433.0 and 435.0 [M+H]⁺.

N4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamine

A Schlenk tube was charged with2-chloro-N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-5-fluoropyrimidin-4-amine(0.1027 g, 0.2368 mmol), benzophenone imine (0.04751 ml, 0.2842 mmol),tris(dibenzylideneacetone)-dipalladium (0) (0.05421 g, 0.05920 mmol),rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.1106 g, 0.1776 mmol),sodium tert-butoxide (0.03186 g, 0.3315 mmol), and 2 ml of toluene, andthe mixture was purged with argon and stirred at 80° C. After 19.5 hr,the mixture was cooled to room temperature and diluted with Et₂O (40ml), filtered, rinsed with Et₂O (40 ml), and concentrated under reducedpressure to giveN4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-N2-(diphenylmethylene)-5-fluoropyrimidine-2,4-diamineas an orange syrup: LC-MS m/z 578.0 and 580.1 [M+H]⁺. The orange syrupwas carried on crude without purification for the next step.

To a solution ofN4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-N2-(diphenylmethylene)-5-fluoropyrimidine-2,4-diamine(0.1370 g, 0.237 mmol) in 6 ml of MeOH at room temperature was addedsodium acetate anhydrous (0.0661 g, 0.805 mmol) followed byhydroxylamine hydrochloride (0.0461 g, 0.663 mmol), the mixture wasstirred at room temperature for 15 hr. Then mixture was heated underreflux. After 6 hr at 70° C., the mixture was concentrated under reducedpressure. The crude residue was purified by column chromatography on a40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in Hexane over14 min and then 100% isocratic of EtOAc for 10 min as eluent to giveN4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamineas a yellow syrup and the yellow syrup was purified by semi-prep-HPLC ona Gemini™ 10 μL C18 column (250×21.2 mm, 10 um) using 10-90% gradient ofCH₃CN (0.1% of TFA) in water (0.1% of TFA) over 28 min as eluent to givethe desired product as a TFA salt. The purified product as a TFA saltwas treated with saturated NaHCO₃ (20 ml) and extracted with CH₂Cl₂ (30ml×2). The combined organic layers were washed with H₂O (30 ml×2), driedover Na₂SO₄, filtered, concentrated under reduced pressure to giveN4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamineas a light yellow film: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.38 (1H, s),8.07 (1H, dd, J=8.4, 1.2 Hz), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.48-7.67(7H, m), 5.76 (2H, br. s.), 4.42 (2H, d, J=19.4 Hz); LC-MS (ESI) m/z414.0 and 416.0 [M+H]⁺.

Biological Assays Recombinant Expression of PI3Ks

Full length p110 subunits of PI3K α, β and δ, N-terminally labeled withpolyHis tag, were coexpressed with p85 with Baculo virus expressionvectors in sf9 insect cells. P110/p85 heterodimers were purified bysequential Ni-NTA, Q-HP, Superdex-100 chromatography. Purified α, β andδ isozymes were stored at −20° C. in 20 mM Tris, pH 8, 0.2M NaCl, 50%glycerol, 5 mM DTT, 2 mM Na cholate. Truncated PI3Kγ, residues 114-1102,N-terminally labeled with polyHis tag, was expressed with Baculo virusin Hi5 insect cells. The γ isozyme was purified by sequential Ni-NTA,Superdex-200, Q-HP chromatography. The γ isozyme was stored frozen at−80° C. in NaH₂PO₄, pH 8, 0.2M NaCl, 1% ethylene glycol, 2 mMβ-mercaptoethanol.

Alpha Beta Delta gamma 50 mM Tris pH 8 pH 7.5 pH 7.5 pH 8 MgCl2 15 mM 10mM 10 mM 15 mM Na cholate 2 mM 1 mM 0.5 mM 2 mM DTT 2 mM 1 mM 1 mM 2 mMATP 1 uM 0.5 uM 0.5 uM 1 uM PIP2 none 2.5 uM 2.5 uM none time 1 hr 2 hr2 hr 1 hr [Enzyme] 15 nM 40 nM 15 nM 50 nM

In vitro enzyme assays.

Assays were performed in 25 μL with the above final concentrations ofcomponents in white polypropylene plates (Costar 3355). Phospatidylinositol phosphoacceptor, PtdIns(4,5)P2 P4508, was from EchelonBiosciences. The ATPase activity of the alpha and gamma isozymes was notgreatly stimulated by PtdIns(4,5)P2 under these conditions and wastherefore omitted from the assay of these isozymes. Test compounds weredissolved in dimethyl sulfoxide and diluted with three-fold serialdilutions. The compound in DMSO (1 μL) was added per test well, and theinhibition relative to reactions containing no compound, with andwithout enzyme was determined. After assay incubation at roomtemperature, the reaction was stopped and residual ATP determined byaddition of an equal volume of a commercial ATP bioluminescence kit(Perkin Elmer EasyLite) according to the manufacturer's instructions,and detected using a AnalystGT luminometer.

Compound IC50 2-chloro-N-((8-chloro-2-(2-chlorophenyl)-3-quinolinyl)-3.233255 methyl)-5-fluoro-4-pyrimidinamineN4-((8-chloro-2-(2-chlorophenyl)-3-quinolinyl)methyl)- 0.9132995-fluoro-2,4-pyrimidinediamine4-(((8-chloro-2-(2-chlorophenyl)-3-quinolinyl)sulfonyl)- >40.000000amino)-2-pyridinecarboxamide4-(((2-(2-chlorophenyl)-8-methyl-3-quinolinyl)methyl)- 15.25396amino)-2-pyridinecarboxamide6-chloro-N-((8-chloro-2-phenyl-3-quinolinyl)methyl)-5- 0.724173methoxy-4-pyrimidinamine5-chloro-N4-((1S)-1-(8-chloro-2-(2-pyridinyl)-3- 0.105919quinolinyl)ethyl)-2,4-pyrimidinediamine

Human B Cells Proliferation Stimulate by Anti-IgM Isolate Human B Cells:

Isolate PBMCs from Leukopac or from human fresh blood. Isolate human Bcells by using Miltenyi protocol and B cell isolation kit II.—human Bcells were Purified by using AutoMacs.column.

Activation of Human B Cells

Use 96 well Flat bottom plate, plate 50000/well purified B cells in Bcell proliferation medium (DMEM+5% FCS, 10 mM Hepes, 50 μM2-mercaptoethanol); 150 μL medium contain 250 ng/1 mL CD40L-LZrecombinant protein (Amgen) and 2 μg/mL anti-Human IgM antibody (JacksonImmunoReseach Lab.#109-006-129), mixed with 50 μL B cell mediumcontaining PI3K inhibitors and incubate 72 h at 37° C. incubator. After72 h, pulse labeling B cells with 0.5-1 uCi/well ³H thymidine forovernight ˜18 h, and harvest cell using TOM harvester.

Human B Cells Proliferation stimulate by IL-4

Isolate Human B Cells:

Isolate human PBMCs from Leukopac or from human fresh blood. Isolatehuman B cells using Miltenyi protocol-B cell isolation kit. Human Bcells were Purified by AutoMacs.column.

Activation of Human B Cells

Use 96-well flat bottom plate, plate 50000/well purified B cells in Bcell proliferation medium (DMBM+5% FCS, 50 μM 2-mercaptoethanol, 10 mMHepes). The medium (150 μL) contain 250 ng/mL CD40L-LZ recombinantprotein (Amgen) and 10 ng/mL IL-4 (R&D system # 204-IL-025), mixed with50 150 μL B cell medium containing compounds and incubate 72 h at 37° C.incubator. After 72 h, pulse labeling B cells with 0.5-1 uCi/well 3Hthymidine for overnight ˜18 h, and harvest cell using TOM harvester.

Specific T Antigen (Tetanus Toxoid) Induced Human PBMC ProliferationAssays

Human PBMC are prepared from frozen stocks or they are purified fromfresh human blood using a Ficoll gradient. Use 96 well round-bottomplate and plate 2×10⁵ PBMC/well with culture medium (RPMI1640+10% FCS,50 uM 2-Mercaptoethanol, 10 mM Hepes). For IC₅₀ determinations, PI3Kinhibitors was tested from 10 μM to 0.001 μM, in half log increments andin triplicate. Tetanus toxoid, T cell specific antigen (University ofMassachusetts Lab) was added at 1 μg/mL and incubated 6 days at 37° C.incubator. Supernatants are collected after 6 days for IL2 ELISA assay,then cells are pulsed with ³H-thymidine for ˜18 h to measureproliferation.

GFP Assays for Detecting Inhibition of Class Ia and Class III Pi3K

AKT1 (PKBa) is regulated by Class Ia PI3K activated by mitogenic factors(IGF-1, PDGF, insulin, thrombin, NGF, etc.). In response to mitogenicstimuli, AKT1 translocates from the cytosol to the plasma membrane

Forkhead (FKHRL1) is a substrate for AKT1. It is cytoplasmic whenphosphorylated by AKT (survival/growth). Inhibition of AKT(stasis/apoptosis)-forkhead translocation to the nucleus

FYVE domains bind to PI(3)P. the majority is generated by constitutiveaction of PI3K Class III

AKT Membrane Ruffling Assay (CHO-IR-AKTI-EGFP Cells/GE Healthcare)

Wash cells with assay buffer. Treat with compounds in assay buffer 1 h.Add 10 ng/mL insulin. Fix after 10 min at room temp and image

Forkhead Translocation Assay (MDA MB468 Forkhead-DiversaGFP Cells)

Treat cells with compound in growth medium 1 h. Fix and image.

Class III PI(3)P Assay (U2OS EGFP-2×FYVE Cells/GE Healthcare)

Wash cells with assay buffer. Treat with compounds in assay buffer 1 h.Fix and image.

Control for All 3 Assays is 10 uM Wortmannin:

AKT is cytoplasmic

Forkhead is nuclear

PI(3)P depleted from endosomes

Biomarker Assay: B-Cell Receptor Stimulation of CD69 or B7.2 (CD86)Expression

Heparinized human whole blood was stimulated with 10 μg/mL anti-IgD(Southern Biotech, #9030-01). 90 μL of the stimulated blood was thenaliquoted per well of a 96-well plate and treated with 10 μL of variousconcentrations of blocking compound (from 10-0.0003 μM) diluted inIMDM+10% FBS (Gibco). Samples were incubated together for 4 h (for CD69expression) to 6 h (for B7.2 expression) at 37° C. Treated blood (50 μL)was transferred to a 96-well, deep well plate (Nunc) for antibodystaining with 10 μL each of CD45-PerCP (BD Biosciences, #347464),CD19-FITC (BD Biosciences, #340719), and CD69-PE (BD Biosciences,#341652). The second 50 μL of the treated blood was transferred to asecond 96-well, deep well plate for antibody staining with 10 μL each ofCD19-FITC (BD Biosciences, #340719) and CD86-PeCy5 (BD Biosciences,#555666). All stains were performed for 15-30 minutes in the dark atroom temperature. The blood was then lysed and fixed using 450 μL ofFACS lysing solution (BD Biosciences, #349202) for 15 minutes at roomtemperature. Samples were then washed 2× in PBS+2% FBS before FACSanalysis. Samples were gated on either CD45/CD19 double positive cellsfor CD69 staining, or CD19 positive cells for CD86 staining.

Gamma Counterscreen: Stimulation of Human Monocytes for Phospho-AKTExpression

A human monocyte cell line, THP-1, was maintained in RPMI+10% FBS(Gibco). One day before stimulation, cells were counted using trypanblue exclusion on a hemocytometer and suspended at a concentration of1×10⁶ cells per mL of media. 100 μL of cells plus media (1×10⁵ cells)was then aliquoted per well of 4-96-well, deep well dishes (Nunc) totest eight different compounds. Cells were rested overnight beforetreatment with various concentrations (from 10-0.0003 μM) of blockingcompound. The compound diluted in media (12 μL) was added to the cellsfor 10 minutes at 37° C. Human MCP-1 (12 μL, R&D Diagnostics, #279-MC)was diluted in media and added to each well at a final concentration of50 ng/mL. Stimulation lasted for 2 minutes at room temperature.Pre-warmed FACS Phosflow Lyse/Fix buffer (1 mL of 37° C.) (BDBiosciences, #558049) was added to each well. Plates were then incubatedat 37° C. for an additional 10-15 minutes. Plates were spun at 1500 rpmfor 10 minutes, supernatant was aspirated off, and 1 mL of ice cold 90%MeOH was added to each well with vigorous shaking. Plates were thenincubated either overnight at −70° C. or on ice for 30 minutes beforeantibody staining. Plates were spun and washed 2× in PBS+2% FBS (Gibco).Wash was aspirated and cells were suspended in remaining buffer. RabbitpAKT (50 μL, Cell Signaling, #4058L) at 1:100, was added to each samplefor 1 h at rt with shaking. Cells were washed and spun at 1500 rpm for10 minutes. Supernatant was aspirated and cells were suspended inremaining buffer. Secondary antibody, goat anti-rabbit Alexa 647 (50 μL,Invitrogen, #A21245) at 1:500, was added for 30 minutes at rt withshaking. Cells were then washed 1× in buffer and suspended in 150 μL ofbuffer for FACS analysis. Cells need to be dispersed very well bypipetting before running on flow cytometer. Cells were run on an LSR II(Becton Dickinson) and gated on forward and side scatter to determineexpression levels of pAKT in the monocyte population.

Gamma Counterscreen: Stimulation of Monocytes for Phospho-AKT Expressionin Mouse Bone Marrow

Mouse femurs were dissected from five female BALB/c mice (Charles RiverLabs.) and collected into RPMI+10% FBS media (Gibco). Mouse bone marrowwas removed by cutting the ends of the femur and by flushing with 1 mLof media using a 25 gauge needle. Bone marrow was then dispersed inmedia using a 21 gauge needle. Media volume was increased to 20 mL andcells were counted using trypan blue exclusion on a hemocytometer. Thecell suspension was then increased to 7.5×10⁶ cells per 1 mL of mediaand 100 μL (7.5×10⁵ cells) was aliquoted per well into 4-96-well, deepwell dishes (Nunc) to test eight different compounds. Cells were restedat 37° C. for 2 h before treatment with various concentrations (from10-0.0003 μM) of blocking compound. Compound diluted in media (12 μL)was added to bone marrow cells for 10 minutes at 37° C. Mouse MCP-1 (12μL, R&D Diagnostics, #479-JE) was diluted in media and added to eachwell at a final concentration of 50 ng/mL. Stimulation lasted for 2minutes at room temperature. 1 mL of 37° C. pre-warmed FACS PhosflowLyse/Fix buffer (BD Biosciences, #558049) was added to each well. Plateswere then incubated at 37° C. for an additional 10-15 minutes. Plateswere spun at 1500 rpm for 10 minutes. Supernatant was aspirated off and1 mL of ice cold 90% MeOH was added to each well with vigorous shaking.Plates were then incubated either overnight at −70° C. or on ice for 30minutes before antibody staining. Plates were spun and washed 2× inPBS+2% FBS (Gibco). Wash was aspirated and cells were suspended inremaining buffer. Fc block (2 μL, BD Pharmingen, #553140) was then addedper well for 10 minutes at room temperature. After block, 50 μL ofprimary antibodies diluted in buffer; CD11b-Alexa488 (BD Biosciences,#557672) at 1:50, CD64-PE (BD Biosciences, #558455) at 1:50, and rabbitpAKT (Cell Signaling, #4058L) at 1:100, were added to each sample for 1h at RT with shaking. Wash buffer was added to cells and spun at 1500rpm for 10 minutes. Supernatant was aspirated and cells were suspendedin remaining buffer. Secondary antibody; goat anti-rabbit Alexa 647 (50μL, Invitrogen, #A21245) at 1:500, was added for 30 minutes at rt withshaking. Cells were then washed 1× in buffer and suspended in 100 μL ofbuffer for FACS analysis. Cells were run on an LSR II (Becton Dickinson)and gated on CD11b/CD64 double positive cells to determine expressionlevels of pAKT in the monocyte population.

pAKT In Vivo Assay

Vehicle and compounds are administered p.o. (0.2 mL) by gavage (OralGavage Needles Popper & Sons, New Hyde Park, N.Y.) to mice (TransgenicLine 3751, female, 10-12 wks Amgen Inc, Thousand Oaks, Calif.) 15 minprior to the injection i.v (0.2 mls) of anti-IgM FITC (50 ug/mouse)(Jackson Immuno Research, West Grove, Pa.). After 45 min the mice aresacrificed within a CO₂ chamber. Blood is drawn via cardiac puncture(0.3 mL) (1 cc 25 g Syringes, Sherwood, St. Louis, Mo.) and transferredinto a 15 mL conical vial (Nalge/Nunc International, Denmark). Blood isimmediately fixed with 6.0 mL of BD Phosflow Lyse/Fix Buffer (BDBioscience, San Jose, Calif.), inverted 3×'s and placed in 37° C. waterbath. Half of the spleen is removed and transferred to an eppendorf tubecontaining 0.5 mL of PBS (Invitrogen Corp, Grand Island, N.Y.). Thespleen is crushed using a tissue grinder (Pellet Pestle, Kimble/Kontes,Vineland, N.J.) and immediately fixed with 6.0 mL of BD PhosflowLyse/Fix buffer, inverted 3×'s and placed in 37° C. water bath. Oncetissues have been collected the mouse is cervically-dislocated andcarcass to disposed. After 15 min, the 15 mL conical vials are removedfrom the 37° C. water bath and placed on ice until tissues are furtherprocessed. Crushed spleens are filtered through a 70 gm cell strainer(BD Bioscience, Bedford, Mass.) into another 15 mL conical vial andwashed with 9 mL of PBS. Splenocytes and blood are spun @ 2,000 rpms for10 min (cold) and buffer is aspirated. Cells are resuspended in 2.0 mLof cold (−20° C.) 90% methyl alcohol (Mallinckrodt Chemicals,Phillipsburg, N.J.). Methanol is slowly added while conical vial israpidly vortexed. Tissues are then stored at −20° C. until cells can bestained for FACS analysis.

Multi-Dose TNP Immunization

Blood was collected by retro-orbital eye bleeds from 7-8 week old BALB/cfemale mice (Charles River Labs.) at day 0 before immunization. Bloodwas allowed to clot for 30 minutes and spun at 10,000 rpm in serummicrotainer tubes (Becton Dickinson) for 10 minutes. Sera werecollected, aliquoted in Matrix tubes (Matrix Tech. Corp.) and stored at−70° C. until ELISA was performed. Mice were given compound orallybefore immunization and at subsequent time periods based on the life ofthe molecule. Mice were then immunized with either 50 μg of TNP-LPS(Biosearch Tech., #T-5065), 50 μg of TNP-Ficoll (Biosearch Tech.,#F-1300), or 100 μg of TNP-KLH (Biosearch Tech., #T-5060) plus 1% alum(Brenntag, #3501) in PBS. TNP-KLH plus alum solution was prepared bygently inverting the mixture 3-5 times every 10 minutes for 1 hourbefore immunization. On day 5, post-last treatment, mice were CO₂sacrificed and cardiac punctured. Blood was allowed to clot for 30minutes and spun at 10,000 rpm in serum microtainer tubes for 10minutes. Sera were collected, aliquoted in Matrix tubes, and stored at−70° C. until further analysis was performed. TNP-specific IgG1, IgG2a,IgG3 and IgM levels in the sera were then measured via ELISA. TNP-BSA(Biosearch Tech., #T-5050) was used to capture the TNP-specificantibodies. TNP-BSA (10 μg/mL) was used to coat 384-well ELISA plates(Corning Costar) overnight. Plates were then washed and blocked for 1 husing 10% BSA ELISA Block solution (KPL). After blocking, ELISA plateswere washed and sera samples/standards were serially diluted and allowedto bind to the plates for 1 h. Plates were washed and Ig-HRP conjugatedsecondary antibodies (goat anti-mouse IgG1, Southern Biotech #1070-05,goat anti-mouse IgG2a, Southern Biotech #1080-05, goat anti-mouse IgM,Southern Biotech #1020-05, goat anti-mouse IgG3, Southern Biotech#1100-05) were diluted at 1:5000 and incubated on the plates for 1 h.TMB peroxidase solution (SureBlue Reserve TMB from KPL) was used tovisualize the antibodies. Plates were washed and samples were allowed todevelop in the TMB solution approximately 5-20 minutes depending on theIg analyzed. The reaction was stopped with 2M sulfuric acid and plateswere read at an OD of 450 nm.

For the treatment of PI3Kδ-mediated-diseases, such as rheumatoidarthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis,psoriasis, inflammatory diseases, and autoimmune diseases, the compoundsof the present invention may be administered orally, parentally, byinhalation spray, rectally, or topically in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles. The term parenteral as used herein includes, subcutaneous,intravenous, intramuscular, intrasternal, infusion techniques orintraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,psoriatic arthritis, psoriasis, inflammatory diseases, and autoimmunediseases and the like.

The dosage regimen for treating PI3Kδ-mediated diseases, cancer, and/orhyperglycemia with the compounds of this invention and/or compositionsof this invention is based on a variety of factors, including the typeof disease, the age, weight, sex, medical condition of the patient, theseverity of the condition, the route of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. Dosage levels ofthe order from about 0.01 mg to 30 mg per kilogram of body weight perday, preferably from about 0.11 mg to 10 mg/kg, more preferably fromabout 0.25 mg to 1 mg/kg are useful for all methods of use disclosedherein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)-alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt thereof, wherein: X¹ is C(R⁹) orN; X² is C(R¹⁰) or N; Y is N(R¹¹), O or S; n is 0, 1, 2 or 3; R¹ is adirect-bonded or oxygen-linked saturated, partially-saturated orunsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3or 4 atoms selected from N, O and S, but containing no more than one Oor S, wherein the available carbon atoms of the ring are substituted by0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by 0 or1 R² substituents, and the ring is additionally substituted by 0, 1, 2or 3 substituents independently selected from halo, nitro, cyano,C₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl, N(C₁₋₄alkyl)C₁₋₄alkyland C₁₋₄haloalkyl; R² is selected from halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); or R² is selected from C₁₋₆alkyl, phenyl,benzyl, heteroaryl, heterocycle, —(C₁₋₃alkyl)heteroaryl,—(C₁₋₃alkyl)heterocycle, —O(C₁₋₃alkyl)heteroaryl,—O(C₁₋₃alkyl)heterocycle, —NR^(a)(C₁₋₃alkyl)heteroaryl,—NR^(a)(C₁₋₃alkyl)heterocycle, —(C₁₋₃alkyl)phenyl, —O(C₁₋₃alkyl)phenyland —NR^(a)(C₁₋₃alkyl)phenyl all of which are substituted by 0, 1, 2 or3 substituents selected from C₁₋₄haloalkyl, OC₁₋₄alkyl, Br, Cl, F, I andC₁₋₄alkyl; R³ is selected from H, halo, C₁₋₄haloalkyl, cyano, nitro,—C(═O)R^(a), —C(═O)OR^(a), C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl; R⁴ is, independently, in each instance, halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl or C₁₋₄haloalkyl; R⁵ is, independently, in eachinstance, H, halo, C₁₋₆alkyl, C₁₋₄haloalkyl, or C₁₋₆alkyl substituted by1, 2 or 3 substituents selected from halo, cyano, OH, OC₁₋₄alkyl,C₁₋₄alkyl, C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl; or both R⁵ groups together form a C₃₋₆spiroalkylsubstituted by 0, 1, 2 or 3 substituents selected from halo, cyano, OH,OC₁₋₄alkyl, C₁₋₄alkyl, C₁₋₃haloalkyl, OC₁₋₄alkyl, NH₂, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl; R⁶ is selected from H, C₁₋₆haloalkyl, Br, Cl, F,I, OR^(a), NR^(a)R^(a), C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁷is selected from H, C₁₋₆haloalkyl, Br, Cl, F, I, OR^(a), NR^(a)R^(a),C₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein theC₁₋₆alkyl, phenyl, benzyl, heteroaryl and heterocycle are additionallysubstituted by 0, 1, 2 or 3 substituents selected from C₁₋₆haloalkyl,OC₁₋₆alkyl, Br, Cl, F, I and C₁₋₆alkyl; R⁸ is selected from H, halo,C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), S(═O)R^(a), S(═O)₂R^(a), S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), N(R^(a))C(═O)R^(a),N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a), C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle, wherein the C₁₋₆alkyl, phenyl,benzyl, heteroaryl and heterocycle are additionally substituted by 0, 1,2 or 3 substituents selected from C₁₋₆haloalkyl, OC₁₋₆alkyl, Br, Cl, F,I and C₁₋₆alkyl; R⁹ is selected from H, halo, C₁₋₄haloalkyl, cyano,nitro, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(a), —S(═O)₂N(R^(a))C(═O)OR^(a),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a),—NR^(a)C₂₋₆alkylOR^(a), C₁₋₁₆alkyl, phenyl, benzyl, heteroaryl andheterocycle, wherein the C₁₋₆alkyl, phenyl, benzyl, heteroaryl andheterocycle are additionally substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(a), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a),—S(═O)₂R^(a), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a), —NR^(a)C₂₋₆alkylOR^(a); or R⁹ is asaturated, partially-saturated or unsaturated 5-, 6- or 7-memberedmonocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O andS, but containing no more than one O or S, wherein the available carbonatoms of the ring are substituted by 0, 1 or 2 oxo or thioxo groups,wherein the ring is substituted by 0, 1, 2, 3 or 4 substituents selectedfrom halo, C₁₋₄haloalkyl, cyano, nitro, —C(═O)R^(a), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(a),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(a), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(a), —S(═O)₂R^(a),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),NR^(a)R^(a), N(R^(a))C(═O)R^(a), N(R^(a))C(═O)OR^(a),—N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R¹⁰ is H,C₁₋₃alkyl, C₁₋₃haloalkyl, cyano, nitro, CO₂R^(a), C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(a),—S(═O)₂N(R^(a))C(═O)OR^(a), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), S(═O)R^(b),S(═O)₂R^(b) or S(═O)₂NR^(a)R^(a); R¹¹ is H or C₄alkyl; R^(a) isindependently, at each instance, H or R^(b); and R^(b) is independently,at each instance, phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl andC₁₋₆alkyl being substituted by 0, 1, 2 or 3 substituents selected fromhalo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,—N(C₁₋₄alkyl)C₁₋₄alkyl.
 2. A compound according to claim 1, having thestructure:


3. A compound according to claim 1, having the structure:


4. A compound according to claim 1, having the structure:


5. A compound according to claim 1, wherein R³ is F, Cl or Br; and n is0.
 6. A compound according to claim 1, wherein R¹ is phenyl substitutedby 0 or 1 R² substituents, and the phenyl is additionally substituted by0, 1, 2 or 3 substituents independently selected from halo, nitro,cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.
 7. A compound according to claim1, wherein R¹ is a direct-bonded or oxygen-linked saturated,partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic ringcontaining 1, 2, 3 or 4 atoms selected from N, O and S, but containingno more than one O or S, wherein the available carbon atoms of the ringare substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring issubstituted by 0 or 1 R² substituents, and the ring is additionallysubstituted by 0, 1, 2 or 3 substituents independently selected fromhalo, nitro, cyano, C₁₋₄alkyl, OC₁₋₄alkyl, OC₁₋₄haloalkyl, NHC₁₋₄alkyl,N(C₁₋₄alkyl)C₁₋₄alkyl and C₁₋₄haloalkyl.
 8. A method of treatingrheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriaticarthritis, psoriasis, inflammatory diseases and autoimmune diseases,inflammatory bowel disorders, inflammatory eye disorders, inflammatoryor unstable bladder disorders, skin complaints with inflammatorycomponents, chronic inflammatory conditions, autoimmune diseases,systemic lupus erythematosis (SLE), myestenia gravis, rheumatoidarthritis, acute disseminated encephalomyelitis, idiopathicthrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome andautoimmune hemolytic anemia, allergic conditions and hypersensitivity,comprising the step of administering a compound according to claim
 1. 9.A method of treating cancers, which are mediated, dependent on orassociated with p110δ activity, comprising the step of administering acompound according to claim
 1. 10. A pharmaceutical compositioncomprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.